Subchronic exposure to Tamoxifen modulates the hippocampal BDNF/ERK/Akt/CREB pathway and impairs memory in intact female rats

Long-Term Oral Tamoxifen Administration Decreases Brain-Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats

“…Specifically, tamoxifen injection is associated with decreased progenitor cell proliferation in the dentate gyrus, although tamoxifen ingestion is associated with increased neuronal differentiation in the dentate gyrus. Further, Klann et al (2023) found that long-term intragastric administration of tamoxifen reduced BDNF expression in the hippocampus, along with reductions in downstream signaling via the ERK/Act/CREB cascade [41]. Thus, our finding that long-term oral tamoxifen administration decreased BDNF density in the current study is corroborated by studies using other administration methods and may be due to a decrease in downstream signaling and/or cell proliferation.…”

“…Future studies using this model of long-term oral tamoxifen administration should include behavioral assays of cognition, mood, and anxiety. Indeed, recent work using sub-chronic intragastric administration of tamoxifen in gonad-intact Wistar rats produced deficits in behavioral measures of mood, anxiety, and recognition memory [41]. Our congruent finding that long-term tamoxifen administration decreased BDNF in the DG, CA1, and medial CA3 suggests that pattern separation, spatial memory, associative memory, and episodic memory processes could be particularly affected [52][53][54].…”

“…Voluntary oral administration via medicated food pellets is a clinically relevant, noninvasive, and effective method for modeling the effects of tamoxifen in rodents. Tamoxifen can readily cross the blood-brain barrier [39,40], and oral self-administration is an attractive alternative to systemic injections [14,[16][17][18], oral gavage [15], or intragastric administration [41], in that it more closely models the metabolism of tamoxifen use in patient populations and eliminates stress associated with restraint, repeated injections, or gavage as potential confounding variables. Nonetheless, there are some challenges with this method.…”